The experiments in this proposal embrace 3 aspects of the early development and regeneration of olfactory epithelium: 1) Regulation of neurogenesis and cellular longevity. It is well known that olfactory neurogenesis continues throughout adult life. We know also that the rate of cell proliferation and the life span of neurons can be modulated. These data imply the existence of regulatory factors for neurogenesis and cell longevity. We shall try to determine whether such factors exist within the epithelium. 2a) The cellular substrate along which the olfactory nerve grows to the olfactory bulb. Olfactory nerves grow to their target, the bulb, along a substrate of cells that migrate from the placode. We propose to use immunocytochemical methods to map surface markers (putative guidance cues) on the migrating cells and their relation to the growing axons. 2b) The olfactory neuron is the only nerve cell located outside of the CNS that, in adult mammals, can grow an axon that enters the CNS. This may be related to unique properties of the axon, the substrate, or both. We shall test several tissue substrates for their permissiveness for olfactory axon growth. An understanding of the unique properties of olfactory nerves may be useful in consideration of clinical problems of nerve regeneration in the CNS. 2c) some of the migrating cells from the embryonic olfactory placode are LHRH-positive; these migrate to the terminal nerve ganglion and to the diencephalon. We shall do ablation experiments to determine whether all LHRH neurons in diencephalon originate in the placode. 3a) Regulation of expression of certain molecules in olfactory epithelium. We are interested particularly in the bulbar control of expression of G-proteins and adenylate cyclase in olfactory epithelium. Preliminary data suggest G- protein synthesis is severely depressed when olfactory epithelium is disconnected from the bulb. We shall use in vivo and in vitro techniques to determine whether the presence of the bulb is required for full expression of olfactory specific G-protein and adenylate cyclase, and whether there is functional coupling between the G-protein and adenylate cyclase, and whether there is functional coupling between the G-proteins and adenylate cyclase at the time when they are first expressed in developing and reconstituting epithelia. 3b) We shall isolate and characterize an antigenic determinant identified by one of our monoclonal antibodies. In rat olfactory epithelium, this determinant is expressed uniquely on a non-neuronal cell type, probably a subpopulation of supporting cells.